JP2021526504A - Solifenacin pharmaceutical solid oral dosage form - Google Patents

Abstract

The present invention is a pharmaceutically solid oral dosage form comprising soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein soriphenacin or a pharmaceutical product thereof. With respect to the pharmaceutical solid oral dosage form in which the locally acceptable salt and the ion exchange resin form a matrix and exhibit a dissolution profile according to the following: (i) containing soriphenacine after 5 minutes at pH 6.5-7.5. Less than 10% of the amount dissolves, and (ii) more than 80% of the soriphenacin content dissolves after 30 minutes at pH 1.0-1.6. The present invention also relates to methods of preparation thereof and the use of pharmaceutical solid oral dosage forms in the treatment of lower urinary tract symptoms associated with overactive bladder syndrome.

Description

Cross-reference to related applications This application claims the interests of European Patent Application No. 18382149.5 filed March 8, 2018 and European Patent Application No. 18382472.1 filed June 26, 2018. Is.

The present invention relates to a pharmaceutical solid oral dosage form of solifenacin. More specifically, the present invention relates to a pharmaceutical solid oral dosage form of solifenacin that disintegrates in the oral cavity (buccal capacity) prior to swallowing by a human subject.

Solifenacin is represented by structural formula (I), and its chemical name is (3R) -1-azabicyclo [2.2.2] octane-3-yl- (1S) -1-phenyl-3,4-dihydro-2. (1H) -isoquinoline carboxylate.

Soliphenacin has excellent selective antagonism to the muscarinic M3 receptor, resulting in nervous pollakiuria, neuropathic bladder, overactive bladder, nocturnal urination, unstable bladder, bladder contraction, chronic cystitis, and benign prostatic hyperplasia. It is an effective therapeutic agent for the prevention and treatment of urinary tract symptoms such as lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). On the other hand, soriphenacin can also be used to treat certain respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis.

Orodispersible tablets serve as an alternative dosage form for patients suffering from dysphagia. Such symptoms are of particular importance among the elderly, stroke victims, or patients with dysphagia psychiatric disorders. In addition, since orally disintegrating tablets do not require water, they can be taken in situations where patients cannot easily obtain water, such as when traveling, which contributes to improved treatment adherence.

However, not all drugs are suitable for the design of orally disintegrating tablets, especially those with unpleasant erotic properties or whose absorption through the oral cavity should be limited. In this regard, solifenacin and its salts are known to have a very strong bitter taste, are very convergent, and can cause local numbness when they are absorbed through the oral cavity. Therefore, the design of the orally disintegrating dosage form of solifenacin must be able to overcome all these hurdles.

Patent Document 1 discloses a fast-disintegrating tablet (another name for an orally disintegrating tablet) containing particles containing solifenacin or diphenhydramine in a core, an intermediate layer containing an insolubilizer and an insolubilizer, and an outer layer for controlling the permeation rate of water. doing. However, the orally disintegrating tablet disclosed in Patent Document 1 requires precise control of the time during which drug release is suppressed (delay time), and at the same time, when the delay time elapses, the drug is rapidly released. (Patent Document 1, paragraph [0006]). Unfortunately, it seems difficult and cost-effective to apply such requirements industrially. Moreover, the tablets disclosed in the patent reduce the dissolution of solifenacin in the oral cavity, but do not guarantee its complete suppression.

On the other hand, the stability of the pharmaceutical composition of solifenacin is known to be a concern in the prior art. For example, Patent Document 2 reports that it is difficult to obtain a solifenacin preparation having sufficient stability under a general pharmaceutical manufacturing method. This document reveals that the main cause of solifenacin degradation over time is amorphous solifenacin produced during the manufacturing process of the pharmaceutical, and therefore to avoid the formation of degradation products. , Patent Document 2 proposes to limit the formation of amorphous solifenacin by adjusting the water content during wet granulation of the pharmaceutical product (Patent Document 2, paragraphs [0009] to [0012]).

It has been reported that the main degradation product of solifenacin is solifenacin N-oxide (Patent Document 2, paragraph [0008], and Non-Patent Document 1). The structural formula of solifenacin N-oxide is shown in formula (II), and its chemical name is 1-oxide-1-azabicyclo [2.2.2] octane-3-yl-1-phenyl-3,4-dihydroisoquinoline. -2 (1H) -carboxylate.

Solifenacin N-oxide has been identified as the major non-pharmacological active metabolite of solifenacin. In a multi-dose, open-label crossover study by Krauwinkel et al. (Non-Patent Document 2), approximately 50% of solifenacin was the parent compound (8% -13%) or metabolite (solifenacin N-oxide: 19-29%). , Other metabolites: 9.5% to 16.9%) were recovered in urine. As a result, degradation to solifenacin N-oxide can significantly reduce the efficacy of solifenacin products in the treatment of urinary symptoms.

European Patent Publication No. 1787640A1 European Patent Publication No. 1728791A1

Rami Reddy B. V. , Devopment and Validation of a Special Physical Indicatoring High Performance Liquid Chromatography Database 20 ID 412353, page 7 Klauwinkel W. J. J. , Effect of age on the pharmacokinetics of solifenacin in men and women, Int J Clin Pharmacol Ther. , 2005; Volume 43, pp. 227-238

Therefore, the existing cost of overcoming the problems caused by the partial dissolution of the active ingredient in the oral cavity (eg, bad taste, local numbness, etc.) and at the same time preventing the formation of the main degradation products of solifenacin. The development of an orally disintegrating solid dosage form of solifenacin that can be produced by highly effective pharmaceutical methods remains an open issue. In addition, the requirements for a new formulation of solifenacin, which is bioequivalent to the founder's formulation (Vesicare®, film-coated tablets), make the development of new orally disintegrating solid dosage forms an even more difficult task. ing.

The present inventors show a dissolution profile in which the therapeutically effective amount of solifenacin and the ion exchange resin polymer form a matrix, so that the dosage form substantially prevents the dissolution of solifenacin at oral pH, thereby causing a bad taste. We were able to design a new solid oral dosage form of solifenacin that could avoid problems such as and local numbness.

In addition, we also surprisingly found that the total drug exposure exhibited after a single dose administration of the compositions of the invention was founder's product (Vesicare®, film-coated tablets). ) Was found to be bioequivalent to the total drug exposure obtained after a single dose (unique dose administration). In particular, we surprisingly find that the compositions of the invention exhibit a faster dissolution profile in gastric pH than the founder's product (Vesicale®). Found to be bioequivalent to the referenced product (Vesicale®). This means that the composition of the invention has comparable bioavailability because the rate and degree to which solifenacin is absorbed from the composition of the invention and becomes available at the site of drug action is the same as in the reference sample. means.

The dosage form of the present invention has the ability to disintegrate under oral conditions in human subjects within 3 minutes prior to swallowing, particularly within 2 and a half minutes, more specifically within 2 minutes, more specifically within 1 minute. Therefore, the dosage form of the present invention should be regarded as an orally disintegrating dosage form according to the definition given by the European Pharmacopoeia (Ph. Eur. 6.0, p. 750). In addition, solifenacin does not dissolve due to the dissolution profile they exhibit at oral pH during the time the dosage forms of the invention disintegrate, thus discomfort such as bitterness, dry mouth, or local numbness due to local absorption of solifenacin. Feelings are avoided. Therefore, the dosage forms of the present invention can constitute a valuable therapeutic alternative for patients suffering from urinary tract symptoms suffering from dysphagia (dysphagia) and can help improve the therapeutic adherence of those patients. ..

For the purposes of the present invention, the disintegration time was measured using the European Pharmacopoeia Disintegrator A, placing the dosage form in phosphate buffer with pH = 7 at 37 ° C. and 30 cycles per minute. ..

We also disclose that amorphous solifenacin is a major cause of the formation of solifenacin degradation products, despite the teachings of European Patent Publication No. 1728791A1, the polymer and solifenacin form a matrix. However, it has been found that in embodiments of dosage forms containing amorphous solifenacin or other pharmaceutically acceptable salts thereof in a content of greater than 77%, the formation of degradation products such as solifenacin N-oxide is avoided. bottom. Therefore, the present invention also provides a new method for stabilizing a formulation having a high content of amorphous solifenacin and preventing the formation of decomposition products over time.

Accordingly, a first aspect of the invention is a pharmaceutically solid oral dosage form comprising soriphenacin or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients or carriers. With respect to the pharmaceutical solid oral dosage form, which forms a matrix with the polymer and exhibits the following dissolution profile: Using the European Pharmacopoeia Instrument II (Paddle), the dosage form is placed in 900 mL under appropriate pH conditions. When determined by stirring at 37 ° C. and 50 rpm, the dosage form is (i) after 5 minutes at pH 6.5-7.5, less than 10 w / w% of the soriphenacin content dissolves, and (ii). After 30 minutes at pH 1.0-1.6, more than 80 w / w% of the soriphenacin content dissolves.

A second aspect of the invention relates to a method for preparing a dosage form as defined in the first aspect of the invention, which comprises the following steps: (a) soriphenacin or a pharmaceutically acceptable salt and polymer thereof in water. Steps of preparing a mixture with, (b) one or more diluents, and optionally one or more binders, disintegrants, sweeteners, flavors, or other excipients or carriers. , (C) The mixture of step (b) is granulated by adding the liquid mixture of step (a) to obtain wet granules, and (d) the wet granules obtained in step (c) are dried. The dried granules obtained in the step (e) step (d) are subjected to one or more lubricants, and optionally one or more diluents, binders, disintegrants, and sweeteners. And a step of mixing with a flavoring agent or other excipient or carrier, (f) a step of compressing the mixture obtained in step (e) to form a solid oral dosage form.
A third aspect of the invention relates to a pharmaceutical solid oral dosage form obtained by the method defined in the second aspect of the invention, the pharmaceutical solid oral dosage form exhibiting the following dissolution profile: European Pharmacopoeia. When the dosage form is placed in 900 mL under appropriate pH conditions using a method device II (paddle) and determined with stirring at 37 ° C. and 50 rpm, the dosage form is (i) pH 6.5-5. After 5 minutes at 7.5, less than 10% of the soriphenacin content dissolves, and (ii) after 30 minutes at pH 1.0-1.6, more than 80% of the soriphenacin content dissolves.

A fourth aspect of the present invention is the first or first aspect of the present invention for use in the treatment of lower urinary tract symptoms associated with overactive bladder syndrome such as urgency incontinence, increased urinary frequency and increased urinary urgency. With respect to the dosage form defined in the third aspect.

In particular, one aspect of the invention is orally disintegrating, comprising a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers. A pharmaceutical solid dosage form, characterized in that soriphenacin or a pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, and the dosage form exhibits a dissolution profile according to the following. For disintegrating pharmaceutical solid dosage forms: Using the European Pharmacopoeia Instrument II (paddle), the dosage forms are placed in 900 mL under appropriate pH conditions and determined with stirring at 37 ° C. and 50 rpm (i). ) After 5 minutes at pH 6.5-7.5, less than 10 w / w% of the soriphenacin content dissolves, and (ii) after 30 minutes at pH 1.0-1.6, 80 w / w% of the soriphenacin content. Super dissolves.

The PXRD differential gram of the dried API-resin mixture is shown. The intensity (I) is expressed in arbitrary units (au), and the 2-seater angle (2θ) is expressed in degrees (°). The dissolution profile of the pharmaceutical product 3 (Form3) defined in Example 1 as compared with the film-coated tablet (FCT) of Vesicare® at oral pH is shown. The dissolution rate (D%) is expressed in w / w%, and the time (t) is expressed in minutes (min). The dissolution profile of the formulation 4 (Form4) defined in Example 1 as compared to the film-coated tablets (FCT) of Vescale® at gastric pH is shown. The dissolution rate (D%) is expressed in w / w%, and the time (t) is expressed in minutes (min). For the reference product Vegetablee® 10 mg (Ref-R, circle) and the test product (Test-T, square), the mean plasma concentration (MPC) vs. time (t) curve of solifenacin calculated in Example 8. Shown. The average plasma concentration (MPC) is expressed in ng / mL and the time (t) is expressed in time (h).

Detailed Description of the Invention The term "solifenacin" as used herein is defined as the molecules represented by structural formula (I), but also as pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of solifenacin include either a wide range of inorganic and organic acids. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid, as well as formic acid, acetic acid, propionic acid, oxalic acid, malon. Includes acid addition salts with organic acids such as acids, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, or glutamate.

The term "polymer" as used herein is suitable for forming a matrix with solifenacin or a pharmaceutically acceptable salt thereof, which modifies the dissolution profile of solifenacin or a pharmaceutically acceptable salt thereof. Defined as any pharmaceutically acceptable polymer. As used herein, the term polymer refers to hydrophilic polymers such as hydroxypropylmethylcellulose (HPMC), methylcellulose, sodium carboxymethylcellulose, hydrophobic polymers such as ethylcellulose, and above all, sulfonated styrene-divinylbenzene copolymers, methacrylic acid. -Contains water-insoluble polyelectrolytes such as ion exchange resins containing divinylbenzene copolymers.

As used herein, the term "ion exchange resin" is defined as any pharmaceutically acceptable water-insoluble polymer capable of exchanging their mobile ions with ions in the surrounding medium. The terms used herein include, among other things, sodium or potassium salts or partial salts of sulfonated styrene-divinylbenzene copolymers or methacrylate-divinylbenzene copolymers.

As used herein, the term "cation exchange resin" is defined as any pharmaceutically acceptable water-insoluble polymer capable of exchanging their mobile cations with cations in the surrounding medium. The terms used herein include, among other things, the sodium or potassium salts of sulfonated styrene-divinylbenzene copolymers or methacrylate-divinylbenzene copolymers or partial sodium or potassium salts.

As used herein, the term "acidic cation exchange resin" is any pharmaceutical that can exchange those mobile cations with cations in the ambient medium and has acidic functional groups such as sulfonic acid groups or carboxylic acid groups. Defined as an acceptable water-insoluble polymer. The terms used herein include, among other things, the sodium or potassium salts of sulfonated styrene-divinylbenzene copolymers or methacrylate-divinylbenzene copolymers or partial sodium or potassium salts.

As used herein, the term "weakly acidic cation exchange resin" can exchange those mobile cations with cations in the ambient medium and has any pharmaceutically acceptable weakly acidic functional group such as a carboxylic acid group. Is defined as a water-insoluble polymer. The terms used herein include, among other things, the sodium or potassium salts of the methacrylic acid-divinylbenzene copolymer or the partial sodium or potassium salts.

As used herein, the term "polacryrin potassium" is defined as a partial potassium salt of a methacrylic acid-divinylbenzene copolymer in which a weakly acidic salt is formed from the carboxylic acid functional group of methacrylic acid. Hereinafter, the term "partial polariline potassium" has been commercialized, among other things, under several trade names such as Purple (registered trademark) C115KMR and Amberlite (registered trademark) IRP88.

As used herein, the term "matrix" is defined as a combination of a polymer with soliphenacin or a pharmaceutically acceptable salt thereof, and soriphenacin or a pharmaceutically acceptable salt thereof is, among other things, electrostatically compatible. It is bound to the polymer by action, hydrogen bonds, and intermolecular forces such as van der Waals forces. In particular, when the polymer is an ion exchange resin, solifenacin or a pharmaceutically acceptable salt thereof is bound primarily by electrostatic interaction. More specifically, when the polymer is a cation exchange resin, solifenacin is attached to the negatively charged functional groups of the cation exchange resin, primarily by electrostatic interaction. More specifically, when the polymer is an acidic cation exchange resin, soriphenacin is attached to the negatively charged acidic functional groups of the acidic cation exchange resin, primarily by electrostatic interaction. More specifically, when the polymer is a methacrylic acid-divinylbenzene copolymer, soriphenacin is attached to the negatively charged carboxylic acid groups of the methacrylic acid-divinylbenzene copolymer, primarily by electrostatic interaction.

As used herein, the term "orally disintegrating tablet" is not intended to disperse rapidly prior to swallowing when placed in the mouth according to the European Pharmacopoeia (Ph. Eur. 6.0, p. 750). Defined as a coated tablet, more precisely, an orally disintegrating tablet disintegrates within 3 minutes in a disintegration test. By this definition, the term orally disintegrating tablet includes, among other things, solid oral dosage forms with different names such as orally disintegrating tablets, orally disintegrating tablets, rapidly disintegrating tablets, rapidly dissolving tablets, and chewable tablets.

As used herein, the term "oral pH" is defined as the pH found in the saliva of a healthy human subject. Such pH usually varies from about 6.5 to about 7.5.

As used herein, the term "stomach pH" is defined as the pH found in the stomach of a fasting, healthy human subject. Such pH typically varies from about 1 to about 1.6.

As used herein, the term "disintegrate" is defined as the action by which a solid dosage form transitions from a solid state to a completely disintegrated state.

The term "complete disintegration" as used herein is defined according to the European Pharmacopoeia (Ph. Eur. 6.0, p. 263) and remains on the screen of the test apparatus, except for insoluble fragments. If a disc is used, or if a disc is used, the residue of the dosage form adhering to its underside is a soft mass, defined as the absence of a clear, hard core. As defined herein, disintegration does not mean complete dissolution of the dosage form or its active pharmaceutical ingredient.

As used herein, the term "dissolution profile" refers to the temporal dissolution of solifenacin from the dosage forms of the invention. Hereinafter, the dissolution profile is measured by the weight of dissolved solifenacin per initial weight of solifenacin in the dosage form and is expressed in weight percent (w / w%). Unless otherwise stated, the dissolution profile is subsequently determined using the European Pharmacopoeia Instrument II (paddle), placing the dosage form in 900 mL under appropriate pH conditions and stirring at 37 ° C. and 50 rpm. Will be done.

As used herein, the term "polacryrin potassium" is defined as a partial potassium salt of a copolymer of methacrylic acid and divinylbenzene, in which a weakly acidic salt is formed from the carboxylic acid functional group of methacrylic acid. Polacrilin potassium has been commercialized, among other things, under several trade names such as Purolite® C115KMR and Amberlite® IRP88.

As used herein, the term "amorphous content" is defined as the ratio of amorphous soriphenacin or its pharmaceutically acceptable salt to the sum of amorphous and crystalline soriphenacin or salts thereof. Hereinafter, the amorphous content is indicated by weight percent (w / w%).

As used herein, the term "normal storage conditions" is defined as conditions with a temperature of 20-30 ° C and a relative humidity of 55-65%.

As used herein, the term "intragranular" refers to the components of a pharmaceutical product that are added in the process steps prior to granulation.

As used herein, the term "extragranular" refers to components added in the post-granulation process.

As used herein, the term "degradation product" or "degradation impurity" is a new formulation due to, for example, the effects of light, temperature, atmospheric oxygen, water vapor, or excipients and / or container closure systems. It is defined as an impurity resulting from a chemical change of the drug substance caused during the manufacture and / or storage of.

The International Council for Harmonization of Pharmaceutical Thresholds for Harmonizations for Human use (ICH) is a guideline for impurities in pharmaceutical products containing new active ingredients. In R2), the threshold value of the decomposition product is set. In the case of solifenacin N-oxide as a degradation product of solifenacin, the qualification threshold is 0.5% by weight of solifenacin N-oxide per weight of solifenacin in the dosage form, which determines the structure. The required threshold (identification threshold) is 0.2% and the required threshold for reporting (reporting threshold) is 0.1%.

Hereinafter, the amount of solifenacin N-oxide present in the dosage form of the present invention is expressed by the weight of solifenacin N-oxide per initial weight of solifenacin in the dosage form, and this amount is expressed in weight percent (w / w%). Indicated by.

As used herein, the term "crosslinking disintegrant" is defined as a crosslinked polymer used as a disintegrant in pharmaceutical compositions. Such cross-linking disintegrants are selected, among other things, from the group of croscarmellose, crospovidone, and starch glycolate.

As used herein, the term "wear degree" refers to the tendency of tablets to chip, crumble, or break during handling. The degree of abrasion is tested according to the European Pharmacopoeia guidelines (Ph. Eur. 6.0, pp. 278-279). Maximum mass losses of 1.0% or less are considered acceptable for most products.

As described above, one aspect of the invention is a pharmaceutically solid oral formulation comprising a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. A dosage form, characterized in that soriphenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form exhibiting a dissolution profile according to the following, an orally disintegrating solid preparation. With respect to the pharmaceutical solid oral dosage form, which is in the form and the polymer is an ion exchange resin: using the European Pharmacopoeia Instrument II (paddle), the dosage form is placed in 900 mL under appropriate pH conditions. After 5 minutes at 37 ° C. and 50 rpm, (i) pH 6.5-7.5, less than 10 w / w% of the soriphenacin content dissolves, and (ii) pH 1.0- After 30 minutes at 1.6, more than 80 w / w% of the soriphenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to: (i) after 5 minutes at pH 6.5-7.5. Less than 10 w / w% of solifenacin content dissolves, and (ii) more than 80 w / w% of solifenacin content dissolves after 30 minutes at pH 1.0-1.6.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to: (i) after 5 minutes at pH 6.5-7.5. Less than 5 w / w% of solifenacin content dissolves, and (ii) more than 80 w / w% of solifenacin content dissolves after 30 minutes at pH 1.0-1.6.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to: (i) after 5 minutes at pH 6.5-7.5. Less than 3 w / w% of solifenacin content dissolves, and (ii) more than 80 w / w% of solifenacin content dissolves after 30 minutes at pH 1.0-1.6.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to: (i) after 5 minutes at pH 6.5-7.5. Less than 2% of the solifenacin content dissolves, and (ii) more than 80% of the solifenacin content dissolves after 30 minutes at pH 1.0-1.6.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to:
(A) At pH 6.5-7.5, (i) after 5 minutes, less than 10% of the solifenacin content was dissolved.
(Ii) After 15 minutes, less than 20% of the solifenacin content was dissolved and
(Iii) After 30 minutes, less than 45% of the solifenacin content dissolves, and (b) at pH 1.0-1.6, (i) after 30 minutes, more than 80% of the solifenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to:
(A) At pH 6.5-7.5, (i) after 5 minutes, less than 5% of the solifenacin content was dissolved.
(Ii) After 15 minutes, less than 10% of the solifenacin content was dissolved and
(Iii) After 30 minutes, less than 40% of the solifenacin content dissolves, and (b) at pH 1.0-1.6, (i) after 30 minutes, more than 80% of the solifenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to:
(A) At pH 6.5-7.5, (i) after 5 minutes, less than 3% of the solifenacin content was dissolved.
(Ii) After 15 minutes, less than 6% of the solifenacin content was dissolved and
(Iii) After 30 minutes, less than 25% of the solifenacin content dissolves, and (b) at pH 1.0-1.6, (i) after 30 minutes, more than 80% of the solifenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to:
(A) At pH 6.5-7.5, (i) after 5 minutes, less than 2% of the solifenacin content was dissolved.
(Ii) After 15 minutes, less than 3% of the solifenacin content was dissolved and
(Iii) After 30 minutes, less than 10% of the solifenacin content dissolves, and (b) at pH 1.0-1.6, (i) after 30 minutes, more than 80% of the solifenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to: (i) after 5 minutes at pH 6.5-7.5. Less than 10% of the solifenacin content dissolves, and (ii) more than 85% of the solifenacin content dissolves after 30 minutes at pH 1.0-1.6.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to: (i) after 5 minutes at pH 6.5-7.5. Less than 5% of the solifenacin content dissolves, and (ii) more than 85% of the solifenacin content dissolves after 30 minutes at pH 1.0-1.6.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to: (i) after 5 minutes at pH 6.5-7.5. Less than 3% of the solifenacin content dissolves, and (ii) more than 85% of the solifenacin content dissolves after 30 minutes at pH 1.0-1.6.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to: (i) after 5 minutes at pH 6.5-7.5. Less than 2% of the solifenacin content dissolves, and (ii) more than 85% of the solifenacin content dissolves after 30 minutes at pH 1.0-1.6.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to:
(A) At pH 6.5-7.5, (i) after 5 minutes, less than 10% of the solifenacin content was dissolved.
(Ii) After 15 minutes, less than 20% of the solifenacin content was dissolved and
(Iii) After 30 minutes, less than 45% of the solifenacin content dissolves, and (b) at pH 1.0-1.6, (i) after 30 minutes, more than 85% of the solifenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to:
(A) At pH 6.5-7.5, (i) after 5 minutes, less than 5% of the solifenacin content was dissolved.
(Ii) After 15 minutes, less than 10% of the solifenacin content was dissolved and
(Iii) After 30 minutes, less than 40% of the solifenacin content dissolves, and (b) at pH 1.0-1.6, (i) after 30 minutes, more than 85% of the solifenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to:
(A) At pH 6.5-7.5, (i) after 5 minutes, less than 3% of the solifenacin content was dissolved.
(Ii) After 15 minutes, less than 6% of the solifenacin content was dissolved and
(Iii) After 30 minutes, less than 25% of the solifenacin content dissolves, and (b) at pH 1.0-1.6, (i) after 30 minutes, more than 85% of the solifenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt, polymer thereof, and one or more pharmaceutically acceptable excipients or carriers. , Solifenacin or a pharmaceutically acceptable salt thereof and the polymer form a matrix, the dosage form showing a dissolution profile according to:
(A) At pH 6.5-7.5, (i) after 5 minutes, less than 2% of the solifenacin content was dissolved.
(Ii) After 15 minutes, less than 3% of the solifenacin content was dissolved and
(Iii) After 30 minutes, less than 10% of the solifenacin content dissolves, and (b) at pH 1.0-1.6, (i) after 30 minutes, more than 85% of the solifenacin content dissolves.

In one embodiment, the polymer of the invention is an ion exchange resin, preferably a cation exchange resin, more preferably an acidic or weakly acidic cation exchange resin. In another embodiment, the polymers of the invention are selected from sulfonated styrene-divinylbenzene copolymers and methacrylate-divinylbenzene copolymers. In another embodiment, the polymer of the invention is a partial potassium salt of a methacrylic acid-divinylbenzene copolymer in which a weakly acidic salt is formed from the carboxylic acid functional group of methacrylic acid. In certain embodiments, the polymer is potassium polarkrillin.

In one embodiment, the pharmaceutical solid oral dosage form of the invention is a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Soliphenacin or a pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, and the dosage form shows a dissolution profile according to the following: (i) at pH 6.5-7.5. After 5 minutes, less than 10% of the soriphenacin content dissolves, and after 30 minutes at (ii) pH 1.0-1.6, more than 80% of the soriphenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention is a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Soliphenacin or a pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, and the dosage form shows a dissolution profile according to the following: (i) at pH 6.5-7.5. After 5 minutes, less than 10% of the soriphenacin content dissolves, and after 30 minutes at (ii) pH 1.0-1.6, more than 80% of the soriphenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention is a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Soliphenacin or a pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, and the dosage form shows a dissolution profile according to the following: (i) at pH 6.5-7.5. After 5 minutes, less than 10% of the soriphenacin content dissolves, and after 30 minutes at (ii) pH 1.0-1.6, more than 80% of the soriphenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention is a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Soliphenacin or a pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, and the dosage form shows a dissolution profile according to the following: (i) at pH 6.5-7.5. After 5 minutes, less than 10% of the soriphenacin content dissolves, and after 30 minutes at (ii) pH 1.0-1.6, more than 80% of the soriphenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention is a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Soliphenacin or a pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, and the dosage form shows a dissolution profile according to the following: (i) at pH 6.5-7.5. After 5 minutes, less than 5% of the soriphenacin content dissolves, and after 30 minutes at (ii) pH 1.0-1.6, more than 80% of the soriphenacin content dissolves.

In one embodiment, the pharmaceutical solid oral dosage form of the invention is a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Soliphenacin or a pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, and the dosage form shows a dissolution profile according to the following: (i) at pH 6.5-7.5. After 5 minutes, less than 5% of the soriphenacin content dissolves, and after 30 minutes at (ii) pH 1.0-1.6, more than 80% of the soriphenacin content dissolves.

In one embodiment, the solid oral dosage form of the present invention disintegrates at oral pH within 3 minutes, preferably within 2 and a half minutes (about 150 seconds), preferably within 2 minutes, more preferably within 1 minute.

In one embodiment, the solid oral dosage form of the present invention is a tablet. In another embodiment, the solid oral dosage form of the present invention is an orally disintegrating tablet. In another embodiment, the solid oral dosage form of the present invention is a chewable tablet. In yet another embodiment, the solid oral dosage forms of the invention are, among other things, orally disintegrating solid dosage forms such as orally disintegrating tablets, orally disintegrating granules, or oral thin films.

In one embodiment, the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Soliphenacin or a pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, and the solid oral dosage form is within 3 minutes at oral pH, particularly within 2 and a half minutes, more specifically 2 Disintegrating within minutes, and more specifically within 1 minute, the dosage form exhibits a dissolution profile according to: (i) 10% of soriphenacine content after 5 minutes at pH 6.5-7.5. Less than 80% of the soriphenacin content dissolves after 30 minutes at (ii) pH 1.0-1.6.

In one embodiment, the tablets of the invention contain a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Alternatively, the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, and the tablet is prepared at oral pH within 3 minutes, particularly within 2 and a half minutes, more specifically within 2 minutes, and more specifically. Dissolves within 1 minute and the tablet exhibits a dissolution profile according to: (i) After 5 minutes at pH 6.5-7.5, less than 10% of the soriphenacin content dissolves, and (ii). ) After 30 minutes at pH 1.0-1.6, more than 80% of the soriphenacin content dissolves.

In one embodiment, the tablets of the invention contain a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, a cation exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Alternatively, the pharmaceutically acceptable salt thereof and the cation exchange resin form a matrix, and the tablet is prepared at oral pH within 3 minutes, particularly within 2 and a half minutes, more specifically within 2 minutes, and more specifically. Dissolves within 1 minute and the tablet exhibits a dissolution profile according to: (i) After 5 minutes at pH 6.5-7.5, less than 10% of the soriphenacin content dissolves, and (ii). ) After 30 minutes at pH 1.0-1.6, more than 80% of the soriphenacin content dissolves.

In one embodiment, the tablets of the invention are a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an acidic or weakly acidic cation exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Soliphenacin or a pharmaceutically acceptable salt thereof and the acidic or weakly acidic cation exchange resin form a matrix, and the tablet is prepared at oral pH within 3 minutes, particularly within 2 and a half minutes, more particularly. Disintegrating within 2 minutes, and more specifically within 1 minute, the tablet exhibits a dissolution profile according to: (i) 10% of soriphenacin content after 5 minutes at pH 6.5-7.5. Less than 80% dissolves, and (ii) after 30 minutes at pH 1.0-1.6, more than 80% of the soriphenacin content dissolves.

In one embodiment, the tablets of the invention are a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, a partial potassium salt of a methacrylate-divinylbenzene copolymer, and one or more pharmaceutically acceptable excipients. A matrix of soriphenacin or a pharmaceutically acceptable salt thereof containing an agent or carrier and a partial potassium salt of the methacrylate-divinylbenzene copolymer is formed, and the tablet is prepared at oral pH within 3 minutes, particularly 2 and a half minutes. Disintegrates within, more specifically within 2 minutes, and more specifically within 1 minute, the tablet exhibits a dissolution profile according to: (i) after 5 minutes at pH 6.5-7.5. Less than 10% of the soriphenacin content dissolves, and (ii) more than 80% of the soriphenacin content dissolves after 30 minutes at pH 1.0-1.6.
In one embodiment, the tablets of the invention contain a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, polacrylin potassium, and one or more pharmaceutically acceptable excipients or carriers of solifenacin. Alternatively, the pharmaceutically acceptable salt thereof and the potassium poracrylin form a matrix, and the tablet is prepared at oral pH within 3 minutes, particularly within 2 and a half minutes, more specifically within 2 minutes, and in more detail. Dissolves within 1 minute and the tablet exhibits a dissolution profile according to: (i) After 5 minutes at pH 6.5-7.5, less than 10% of the solifenacin content dissolves, and (ii). ) After 30 minutes at pH 1.0-1.6, more than 80% of the solifenacin content dissolves.

We also found that for some embodiments of the dosage form, the dosage form contained an amorphous content of solifenacin or other pharmaceutically acceptable salt thereof in excess of 77%. Furthermore, despite the teachings of European Patent Application No. 1728 791 A1, which discloses that amorphous solifenacin is a major cause of the formation of solifenacin degradation products, we have found that polymers and solifenacin. In the embodiment of the formulation that forms a matrix with and contains an amorphous solifenacin or other pharmaceutically acceptable salt thereof in a content of greater than 77%, the formation of degradation products such as solifenacin N-oxide is avoided. I found that it was done. Therefore, the present invention also provides a new method for stabilizing a formulation having a high content of amorphous solifenacin and preventing the formation of decomposition products over time.

The method for assessing the amorphous content of soriphenacin or a pharmaceutically acceptable salt thereof according to the present invention is generally any method for identifying the crystal structure of soriphenacin or a salt thereof in a composition, for example, powder X-ray. Includes diffraction (PXRD), differential scanning calorimetry (DSC), solid-state nuclear magnetic resonance (NMR), and near-infrared (NIR) spectroscopy. In particular, in order to measure the crystal structure of a drug having a relatively low concentration in a mixed composition with other components, it is preferable to measure the crystal structure by solid-state NMR or NIR spectroscopy. A method for measuring the amorphous content of solifenacin succinate by NIR is described in European Patent Application No. 1728791A1, paragraph [0029]. A method for measuring the amorphous content of solifenacin succinate by solid-state NMR is described in European Patent Application No. 1728791A1, paragraph [0030]. The described method can be readily adapted by one of ordinary skill in the art to measure the amorphous content of other pharmaceutically acceptable salts of solifenacin.

In one embodiment, the dosage form of the invention is greater than 77%, preferably greater than 80%, more preferably greater than 90%, even more preferably 95% amorphous of solifenacin or other pharmaceutically acceptable salt thereof. Included in super content. In certain embodiments, the dosage forms of the invention contain an amorphous content of solifenacin or other pharmaceutically acceptable salt thereof in excess of 99%.

Interestingly, we found that when solifenacin and the polymers of the invention form a matrix, the content of amorphous solifenacin remains temporally stable, avoiding the conversion of amorphous solifenacin to crystalline solifenacin. I also found that.

In one embodiment, the dosage forms of the invention are more than 77%, preferably more than 80%, amorphous of solifenacin or other pharmaceutically acceptable salt thereof after 3 months of storage under normal storage conditions. It is preferably contained in a content of more than 90%, and even more preferably more than 95%. In certain embodiments, the dosage forms of the invention contain an amorphous content of solifenacin or other pharmaceutically acceptable salt thereof in excess of 99% after 3 months of storage under normal storage conditions.

In one embodiment, the solid oral dosage forms of the invention comprising an amorphous content of solifenacin or other pharmaceutically acceptable salt thereof in a content of greater than 77% have a temperature of 20-30 ° C and a relative of 55-65%. After 3 months of storage in humidity, it contains less than 0.5%, preferably less than 0.2%, and more preferably less than 0.1% solifenacin N-oxide.

In another embodiment, solid oral dosage forms of the invention comprising an amorphous of solifenacin or other pharmaceutically acceptable salt thereof in a content of greater than 77% have a temperature of 20-30 ° C and 55-65%. After 6 months of storage in relative humidity, it contains less than 0.5%, preferably less than 0.2%, and more preferably less than 0.1% solifenacin N-oxide.

In another embodiment, the solid oral dosage form of the present invention comprising an amorphous of solifenacin or other pharmaceutically acceptable salt thereof in a content of greater than 77% has a temperature of 30-40 ° C. and 55-65%. After 3 months of storage in relative humidity, it contains less than 0.5%, preferably less than 0.2%, and more preferably less than 0.1% solifenacin N-oxide.

In another embodiment, the solid oral dosage form of the present invention comprising an amorphous of solifenacin or other pharmaceutically acceptable salt thereof in a content of greater than 77% has a temperature of 30-40 ° C. and 55-65%. After 6 months of storage in relative humidity, it contains less than 0.5%, preferably less than 0.2%, and more preferably less than 0.1% solifenacin N-oxide.

In another embodiment, the solid oral dosage form of the present invention comprising an amorphous of solifenacin or other pharmaceutically acceptable salt thereof in a content of greater than 77% has a temperature of 30-40 ° C. and 65-75%. After 3 months of storage in relative humidity, it contains less than 0.5%, preferably less than 0.2%, and more preferably less than 0.1% solifenacin N-oxide.

In another embodiment, the solid oral dosage form of the present invention comprising an amorphous of solifenacin or other pharmaceutically acceptable salt thereof in a content of greater than 77% has a temperature of 30-40 ° C. and 65-75%. After 6 months of storage in relative humidity, it contains less than 0.5%, preferably less than 0.2%, and even more preferably less than 0.1% solifenacin N-oxide.

The amount of solifenacin of the present invention is not particularly limited as long as it is a therapeutically effective amount. Such an amount is preferably 1 to 20 mg, more preferably 1 to 5 mg or 5 to 10 mg, and even more preferably 2.5, 5 or 10 mg of solifenacin succinate or an equivalent amount of other pharmacy thereof. It is an acceptable salt.

Below, all percentages related to the amount of a particular ingredient in a dosage form are shown as the ratio of the weight of the ingredient to the total weight of the dosage form and are expressed in terms of "% by weight component in the dosage form". ..

In another embodiment, the solid oral dosage form of the invention is 0.5-50% by weight of solifenacin, preferably 1-25%, more preferably 1.5-10%, even more preferably 2 in the dosage form. Contains solifenacin in an amount of ~ 5%.

The amount of the polymer of the present invention is not particularly limited as long as solifenacin and the polymer form a matrix having the dissolution profile detailed above.

The weight-to-weight ratio of solifenacin to the polymer is 0.5: 1 to 1:10, preferably 1: 1 to 1: 4, and more preferably 1: 1.5 to 1: 3. In the most preferred embodiment, this ratio is 1: 2.

In another embodiment, the weight-to-weight ratio of the solifenacin to ion or cation exchange resin is 0.5: 1 to 1:10, preferably 1: 1 to 1: 4, and more preferably 1: 1.5 to. It is 1: 3. In the most preferred embodiment, this ratio is 1: 2.

In another embodiment, the weight-to-weight ratio of solifenacin to the acidic or weakly acidic cation exchange resin is 0.5: 1 to 1:10, preferably 1: 1 to 1: 4, and more preferably 1: 1. .5 to 1: 3. In the most preferred embodiment, this ratio is 1: 2.

In another embodiment, the weight-to-weight ratio of solifenacin to the partial potassium salt of the methacrylic acid-divinylbenzene copolymer is 0.5: 1 to 1:10, preferably 1: 1 to 1: 4, and more preferably. It is 1: 1.5 to 1: 3. In the most preferred embodiment, this ratio is 1: 2.

In another embodiment, the weight-to-weight ratio of solifenacin to potassium polacrilin is 0.5: 1 to 1:10, preferably 1: 1 to 1: 4, and more preferably 1: 1.5 to 1. : 3. In the most preferred embodiment, this ratio is 1: 2.

In another embodiment, the solid oral dosage form of the present invention comprises 1.5% to 40% by weight of the polymer in the dosage form, preferably 3% to 15%, more preferably 5% to 10%, and even more. The polymer is preferably contained in an amount of 6% to 7%.

In another embodiment, the solid oral dosage form of the present invention comprises 1.5% to 40% by weight of an ion or cation exchange resin, preferably 3% to 15%, more preferably 5% to 10% in the dosage form. , And even more preferably in an amount of 6% to 7% containing an ion or cation exchange resin.

In another embodiment, the solid oral dosage form of the present invention comprises 1.5% to 40% by weight of an acidic or weakly acidic cation exchange resin in the dosage form, preferably 3% to 15%, more preferably 5% to. It contains an acidic or weakly acidic cation exchange resin in an amount of 10%, and even more preferably 6% to 7%.

In another embodiment, the solid oral dosage form of the present invention is a partial potassium salt of 1.5% to 40% by weight of the methacrylate-divinylbenzene copolymer in the dosage form, preferably 3% to 15%, more preferably. It contains a partial potassium salt of the methacrylate-divinylbenzene copolymer in an amount of 5% to 10%, and even more preferably 6% to 7%.

In another embodiment, the solid oral dosage form of the present invention comprises 1.5% to 40% by weight of potassium polacrilin in the dosage form, preferably 3% to 15%, more preferably 5% to 10%, and. Even more preferably, it contains potassium polariline in an amount of 6% to 7%.

The solid oral dosage forms of the present invention are suitable pharmaceutically acceptable excipients and adjuvants such as diluents, disintegrants, binders, flow promoters, lubricants, and colorants, flavors and sweeteners. Can be further included.

The solid oral dosage form of the present invention may include one or more suitable diluents. Diluents suitable for oral dosage forms are, for example, sugars such as mannitol, lactose, preferably lactose monohydrate, starches and derivatives thereof, and celluloses and derivatives thereof, especially microcrystalline cellulose.

In another embodiment, the oral dosage form of the invention is a diluent of 1 to 80% by weight in the dosage form, preferably 20 to 75%, more preferably 40 to 70%, and even more preferably 50 to 68%. Contains a diluent for.

In another embodiment, the oral dosage form of the invention is 1-80% by weight, preferably 20-75%, more preferably 40-70%, and even more preferably 50-68% mannitol or in the dosage form. Includes lactose or mixtures thereof.

The solid oral dosage form of the present invention may further comprise one or more suitable binders. Suitable binders for oral dosage forms are, for example, sugars such as sucrose, glucose, dextrose, sugar honey and lactose, sodium alginate, gum arabic, polyvinylpyrrolidone (povidone), carboxymethyl cellulose (carmellose), methyl cellulose or hydroxypropyl methyl cellulose. Natural and synthetic polymers such as (hypromellose).

In another embodiment, the oral dosage form of the invention contains 0.05-30% by weight, preferably 1-30%, more preferably 2-30% of the binder in the dosage form.

In another preferred embodiment, the oral dosage form of the invention contains 0.05-30% by weight, preferably 1-30%, more preferably 2-30% hypromellose or lactose or a mixture thereof in the dosage form. do.

The solid oral dosage form of the present invention may further comprise one or more lubricants. Suitable lubricants are, for example, stearic acid and its derivatives, such as calcium stearate, sodium stearyl fumarate or magnesium stearate, among others.

In another embodiment, the lubricant is in an amount of 0.01-2% by weight, preferably 0.1-1.8%, more preferably 0.2-1.6% of the lubricant in the dosage form. Present in solid oral dosage form.

In another preferred embodiment, magnesium stearate has an amount of magnesium stearate of 0.01-2% by weight, preferably 0.1-1.8%, more preferably 0.2-1.6% in the dosage form. Is present in solid oral dosage forms.

The solid oral dosage form of the present invention may further comprise one or more disintegrants. The amount and type of disintegrant can be determined by the solid oral dosage form of the present invention within 3 minutes, especially within 2 and a half minutes, more specifically within 2 minutes, and more specifically within 1 minute at oral pH before swallowing. As long as it is collapsed, it is not particularly limited.

In one embodiment, the disintegrant can be selected from starch, clay, cellulose, algin, gum, and crosslink disintegrant. In a preferred embodiment, the disintegrant is selected from, among other things, a cross-linking disintegrant such as cross-linked carboxymethyl cellulose (croscarmellose), cross-linked polyvinylpolypyrrolidone (crospovidone) or starch glycolate.

In another embodiment, the solid oral dosage form of the present invention comprises one or more disintegrants in a disintegrant amount of 1-35% by weight, preferably 10-30%, more preferably 20-28% of the dosage form. include.

In another embodiment, the solid oral dosage form of the present invention comprises one or more crosslink disintegrations in 1 to 35% by weight, preferably 10 to 30%, more preferably 20 to 28% of the amount of the crosslink disintegrant in the dosage form. Contains agents.

In another embodiment, the solid oral dosage form of the present invention is 1 to 35% by weight, preferably 10 to 30%, and more preferably 20 to 28% of crospovidone or croscarmellose or a mixture thereof in the dosage form. In an amount, it comprises one or more crospovidone or croscarmellose or a mixture thereof.

In another embodiment, the solid oral dosage form of the present invention comprises 1 to 35% by weight, preferably 10 to 30%, and more preferably 20 to 28% of croscarmellose in the dosage form. include.

In a preferred embodiment, the solid oral dosage form of the present invention is 1-10 mg soriphenacin, an ion or cation exchange resin having a weight-to-weight ratio of soriphenacin to the resin, 40-70% by weight. Contains 1 to 30% by weight of binder, 0.1 to 2% by weight of lubricant, and 10 to 30% by weight of crosslink disintegrant.

In another preferred embodiment, the solid oral dosage forms of the invention are 1-10 mg soriphenacin, potassium porakliline having a weight-to-weight ratio of soriphenacin to potassium poracrylin, 40-70. It contains 1 to 30% by weight of diluent, 1 to 30% by weight of binder, 0.1 to 2% by weight of lubricant, and 10 to 30% by weight of cross-linking disintegrant.

In another preferred embodiment, the solid oral dosage forms of the invention are 1-10 mg soriphenacin, potassium porakliline having a weight-to-weight ratio of soriphenacin to potassium poracrylin, 40-70. It contains 1 to 30% by weight of diluent, 1 to 30% by weight of binder, 0.1 to 2% by weight of lubricant, and 10 to 30% by weight of crospovidone or croscarmellose or a mixture thereof.

In one embodiment, the solid oral dosage form of the invention comprises less than 100 mg of lactose, preferably less than 80 mg, and more preferably less than 70 mg of lactose. In this regard, Vesicare®, the reference product of the invention, comprises 107.5 mg lactose monohydrate for 5 mg tablets and 102.5 mg lactose monohydrate for 10 mg tablets. Reducing the amount of lactose in tablets increases the tendency for them to break, chip, or crumble. However, we further produce solid oral dosage forms of solifenacin that contain a lower content of lactose compared to the Veganic reference product while maintaining acceptable wearability values. I was able to do it.

It should be noted that lactose is one of the most commonly used excipients in solid oral dosage form and is usually used as a diluent with binding properties. Although some lactose intolerance has been reported to occur in about 25% of Europeans, small amounts of lactose in medicines are usually considered safe. However, some people may develop gastrointestinal symptoms with low doses of 100-200 mg of lactose (Pawar S., Issues in the formulation of drugs for oral use in children: Role of excipients, Paediator. Year; 4 (6), pp. 371-379). Another study (Eadala P., Quantifying the "hidden" lactose in drugs used for treatment of gastrointestinal conditions, Aliment Pharmacol. It emphasizes that if you are taking multiple medications, therefore cumulative exposure to lactose can occur.

In another embodiment, the solid oral dosage form of the present invention has a weight-to-weight ratio of solifenacin to lactose of 1: 1 to 1:10, preferably 1: 1 to 1: 8, more preferably 1: 1 to 1. It contains lactose at a ratio of 1: 7, and even more preferably 1: 2 to 1: 7.

The present inventors contain a low content of lactose as compared with Vegetablee® (reference product), and at the same time, the allowable value of the degree of abrasion, that is, less than 1%, preferably less than 0.5%, more preferably. Was able to produce a dosage form that maintained less than 0.2% (measured using the abrasion test as disclosed in European Pharmacopoeia 6.0, pp. 278-279).

In another embodiment, the solid oral dosage form of the present invention comprises lactose at a weight-to-weight ratio of solifenacin to lactose, and the solid oral dosage form has a wearability of less than 1%. Shown, preferably 1: 1 to 1: 8 and less than 1% of wear, more preferably 1: 1 to 1: 7 and less than 1% of wear, even more preferably 1: 2 to 1: 7 and 1% of wear. Indicates less than%.

In one embodiment, the solid oral dosage form of the present invention exhibits a hardness of 70 N or less, preferably 60 N or less, and even more preferably 50 N or less.

In one embodiment, the solid oral dosage form of the present invention disintegrates at oral pH within 3 minutes, preferably within 2 and a half minutes (about 150 seconds), preferably within 2 minutes, more preferably within 1 minute, at 70 N. Hereinafter, the hardness is preferably 60 N or less, and even more preferably 50 N or less.

In another embodiment, the solid oral dosage form of the present invention is in an amount of 1 to 35% by weight of the disintegrant, preferably 10 to 30%, more preferably 20 to 28% of the dosage form 1 or 1 or as defined above. It contains a plurality of disintegrants and exhibits a hardness of 70 N or less, preferably 60 N or less, and even more preferably 50 N or less.

In one embodiment, the solid oral dosage form of the present invention disintegrates at oral pH within 3 minutes, preferably within 2 and a half minutes (about 150 seconds), preferably within 2 minutes, more preferably within 1 minute, at 70 N. Hereinafter, the hardness is preferably 60 N or less, still more preferably 50 N or less, and 1 to 35% by weight of the disintegrant in the dosage form, preferably 10 to 30%, more preferably 20 to 28%. Includes one or more disintegrants as defined.

In one embodiment, after a single oral dose, the compositions of the invention have a maximum plasma concentration (C _max ) of 10-20 ng / mL, preferably 12-19 ng / mL, more preferably 14-16 ng / mL. show. The term "C _max " refers to the maximum concentration of solifenacin in the blood after a single oral dose of the composition of the invention.

_{In one embodiment, after a single oral dose, the compositions of the invention have a time (Tmax} ) of 2 to 24 hours, preferably 3 to 11 hours, more preferably 6 to 8 hours to a maximum plasma concentration. Shown, and even more preferably, T _max is 7 hours. The term "T _max " refers to the time, unit of time, to reach _{C max} after a single oral dose of the composition of the invention.

In one embodiment, after a single oral administration, the composition of the present invention _{preferably has a time / plasma concentration curve area (AUC 0-t} ) from time 0 to time t hours of 700 to 1800 ng · hour / mL. Indicates 900 to 1500 ng / hour / mL, more preferably 1100 to 1350 ng / hour / mL, and even more preferably 1150 to 1290 ng / hour / mL.

In one embodiment, after a single oral dose, the compositions of the invention have a time / plasma concentration curve area (AUC _0-∞ ) from time 0 to infinity of 700 to 1900 ng · hour / mL, preferably It represents 1000 to 1600 ng / hour / mL, more preferably 1140 to 1450 ng / hour / mL, and even more preferably 1200 to 1360 ng / hour / mL.

The term "AUC" refers to the area under the curve of time / plasma concentration after a single oral dose of the composition of the invention. AUC _0-∞ indicates the area under the curve of plasma concentration vs. time from time 0 to infinity, and AUC _0-t indicates the area under the curve of plasma concentration vs. time from time 0 to time t.

In one embodiment, after a single oral dose, the compositions of the invention have a half-life of 44-91 hours, preferably 55-80 hours, more preferably 60-73 hours, even more preferably 63-69 (T). _1/2 ) is shown. The term "half-life (T _1/2 )" refers to the time it takes for solifenacin to lose half of its pharmacological activity.

Therefore, we found that the solid oral dosage form of the present invention is the European Medicines Agency (EMA) Guidelines for the Investigation of Bioequivalence (EMA CPMP / EWP / QWP / 1401/98 Rev.1 / Corr). The pharmacokinetic parameters for the bioavailability of soriphenacin described in **) (eg, C _max , T _max , AUC _0-t , AUC _0-∞ , and T _1/2 ) are those of the soriphenashi of the referenced product. Found to show the equivalent. Thereby, the solid oral dosage form of the present invention can be considered bioequivalence to a single dose of Vesicare® in accordance with the guidelines of the European Medicines Agency (EMA).

In one embodiment, the method of preparing a solid oral dosage form of the present invention comprises the following steps:
(A) A step of preparing a mixture of solifenacin or a pharmaceutically acceptable salt thereof in water and a polymer.
(B) The step of mixing one or more diluents and optionally one or more binders, disintegrants, sweets, flavors, or other excipients or carriers.
(C) A step of granulating the mixture of step (b) by adding the liquid mixture of step (a) to obtain wet granules.
(D) A step of drying the wet granules obtained in the step (c) to obtain dried granules.
(E) The dried granules obtained in step (d) are added to one or more lubricants and optionally one or more diluents, binders, disintegrants, sweeteners and flavors, or other additives. The process of mixing with a shaper or carrier,
(F) A step of compressing the mixture obtained in step (e) to form a solid oral dosage form.

All embodiments disclosed above for solid oral dosage forms of the invention also apply to the preparation method.

In a preferred embodiment, the polymer in step (a) is an ion exchange resin, preferably a cation exchange resin, more preferably an acidic or weakly acidic cation exchange resin. In another embodiment, the polymer of step (a) is a methacrylic acid-divinylbenzene copolymer, preferably a partial potassium salt of the methacrylic acid-divinylbenzene copolymer, more preferably potassium polariline.

In a preferred embodiment, one or more disintegrants in steps (b) and (e) are crosslink disintegrants selected from crospovidone, croscarmellose, starch glycolate or mixtures thereof.

The drying step (d) of the method of the present invention can be carried out by any method known in the latest technology for drying granules by a wet granulation method. The drying temperature and duration of the drying method depend on the nature of the active ingredient and the water level required for successful production of satisfactory tablets. Generally, shelf or tray dryers and fluidized bed dryers can be used for this purpose. In one embodiment, the drying step (d) of the method of the invention is carried out under vacuum conditions, preferably at 50-70 ° C, more preferably 55-65 ° C. In general, the term "vacuum condition" refers to a pressure of 0.5 mbar to 3 mbar, preferably including 1-2 mbar.

Solid pharmaceutical dosage forms obtained by the methods defined above are also part of the present invention. For the purposes of the present invention, the expressions "obtained", "obtained" and equivalent expressions are used interchangeably, in which case the expression "obtained" includes the expression "obtained". .. All embodiments disclosed above for steps (a)-(f) of the method of the invention also apply to solid oral dosage forms obtained by this method.

In one embodiment, the pharmaceutical solid oral dosage form defined above is a wet granulated pharmaceutical solid oral dosage form. In the wet granulation method, the powder particles are aggregated using a liquid phase called a binder. In the wet granulation method for preparing the pharmaceutical solid oral dosage form of the present invention defined above, the aggregating step is the soriphenacin obtained in step (a) as a granulation mixture (binder) or pharmaceutically thereof. This is done by the use of an aqueous mixture of acceptable salts and polymers. That is, the method of the present invention does not include the step of drying the solifenacin obtained in step (a) or a mixture of a pharmaceutically acceptable salt thereof and a polymer.

Throughout the description and claims, the word "contains" and its variants are not intended to exclude other technical features, additives, ingredients or processes. Furthermore, the word "including" also includes the case of "consisting of". Additional objectives, advantages and features of the present invention will be apparent to those skilled in the art by examining the description or can be learned by practicing the present invention. The following examples and drawings are provided for illustration purposes only and are not intended to limit the invention. Reference numerals placed in parentheses within the scope of the claims in relation to the drawings are an attempt to increase the clarity of the claims and should be construed as limiting the scope of the claims. is not it. Moreover, the present invention covers all possible combinations of the particular preferred embodiments described herein.

Example 1: Method for producing tablets Solifenacin succinate is dissolved in water with stirring. Once the entire active pharmaceutical ingredient (API) has dissolved and a clear solution is obtained, the resin is added and the resulting API-resin mixture is stirred for 2 hours. The granulation method was carried out with TRI-CHOP MGR-5 (Lreal SA, Spain) using API-resin as the granulation solvent. Next, the obtained granules were sieved through 1 mm. The resulting powder is weighed and yields are obtained to recalculate the required amount of extragranular excipient. All extragranular excipients except lubricants are pre-sieved through 0.630 mm and mixed at 20 rpm for 10 minutes. Sodium stearyl fumarate is added in the final step, previously sieved through 0.630 mm and mixed at 20 rpm for 5 minutes. The final mixture is then compressed using a 10 mm punch.

The dosage forms in Table 1 were obtained according to the manufacturing method described in the previous paragraph.

Example 2: Evaluation of PXRD characteristics of solifenacin-resin complex.
Solifenacin succinate was dissolved in water. Once the entire solifenacin succinate has dissolved, the resin is added and the resulting mixture of API resins is stirred for at least 2 hours. The API-resin mixture was spray dried or dried on a laboratory stove. Finally, the dry mixture of API-resin was analyzed by powder X-ray diffraction (PXRD).

The halo PXRD pattern of FIG. 1 shows that the dosage form of solifenacin of the present invention exists in an amorphous form.

The powdered sample was placed in the recess of the PMMA sample holder and smoothed flat with a glass slide. Special care was taken to avoid excessive pressure. Samples were measured with a Bruker D8 Advance diffractometer using Cu radiation with a primary monochromator (λ = 1.540666A) and a scintillation detector. The measurement conditions used are shown in Table 2.

Example 3: Stability of the pharmaceutical product of the present invention The pharmaceutical product obtained in Example 1 is analyzed and the solifenacin N-oxide present after being stored for a certain period of time under controlled temperature and relative humidity (RH) conditions. The amount was quantified. The results are shown in Table 3.

In all cases, the content of solifenacin N-oxide is the threshold required for safety confirmation established by ICH in the guideline Q3B (R2) regarding impurities in the pharmaceutical products containing new active ingredients. It was well below (0.5%).

Example 4: Dissolution profile of the pharmaceutical product of the present invention at oral pH.
The dissolution profile of the pharmaceutical product 3 obtained in Example 1 and the commercially available film-coated tablet (FCT), Vescale (registered trademark), was measured at oral pH. The results are shown in Table 4 and FIG.

The dissolution profile shows that the dosage forms of the invention have very low release of solifenacin at oral pH, much lower than Vesicare® under the same conditions.

Example 5: Dissolution profile of the pharmaceutical product of the present invention at gastric pH.
The dissolution profile of the pharmaceutical product 4 obtained in Example 1 and the commercially available film-coated tablet (FCT), Vescale (registered trademark), was measured at the pH of the stomach. The results are shown in Table 6 and FIG.

Example 6: Disintegration and Preference Test The pharmaceutical product of the present invention was evaluated by a panel of 10 tasters to evaluate various parameters affecting palatability such as bitterness, dry mouth, and numbness.

The disintegration time was measured according to European Pharmacopoeia Test A (Ph. Eur. 6.0, p. 263), pH = 7, 37 ° C., 30 cycles / min.

According to the definition of orally disintegrating tablets by the European Pharmacopoeia, they must disintegrate in the mouth within 3 minutes before swallowing.

Example 7: Abrasion test and disintegration test of tablets containing low content lactose.
According to the method described in Example 1, the formulations 5 and 6 shown in Table 9 and the formulations 7 and 8 shown in Table 1 having a lactose content of less than 100 mg per tablet were obtained. The formulations shown in Table 9 were subjected to the abrasion degree test according to the guidelines of the European Pharmacopoeia (Ph. Eur. 6.0, pp. 278 to 279). The results are shown in Table 10.

The formulations 5 and 6 shown in Table 9 and the formulations 7 and 8 shown in Table 1 are the European Pharmacopoeia test A (Ph. Eur. 6.0, p. 263), a phosphate buffer solution having a pH of 7. The decay time was tested according to 37 ° C., 30 cycles / min.

As shown in Table 10, all tablets of the formulations 5, 6 and 8 met the requirement of having a degree of abrasion of less than 1% according to the guidelines of the European Pharmacopoeia.

Example 8: Bioavailability test The bioavailability of the solid oral dosage form of the present invention was studied.

A. Methodology In this study, an orally disintegrating tablet of solifenacin succinate 10 mg of the present invention and Astellas Pharma, S. et al. A. 10 mg of Vescare®, a film-coated tablet from Solifenacin, was open-label, balanced, randomized, 2-dose method, 2-dose sequence, 2-stage crossover, and bioavailability. During each study period, 30 blood samples were collected from each subject, including one pre-dose blood sample, excluding missing samples from the discontinued / withdrawn subjects, and the pharmacokinetic profiles of the test and reference products were analyzed. ..

Pharmacokinetic parameters were calculated from the plasma concentration-to-time profile for solifenacin by a non-compartment model using Phoenix® WinNonlin® version 6.4 (Certara LP). Using PROC GLM of SAS® version 9.4 (SAS Institute Inc., USA), statistical comparison of the pharmacokinetic parameters of the two formulations is performed to evaluate the bioavailability between the test and reference formulations. bottom.

B. Number of subjects (planned and analyzed):

C. Key criteria for diagnosis and incorporation:
18-45 years old (including both) with a body mass index (BMI) of 18.5 to 30.0 kg / m2 (including both) who submitted written informed consent to understand and comply with the study procedure. Non-smoking, normal-health adult human volunteers were enrolled in the study. There were no significant disease or clinically significant abnormal findings during screening, medical history, laboratory examination, laboratory evaluation, 12-lead ECG and chest x-ray (posterior-anterior) recording.

D. Samples The samples used in the bioavailability study are:
a) Test sample: Formulation 8 in Table 1 of Example 1.
b) Reference test: Vegetablee® 10 mg, film-coated tablets.

E. Test method Test sample:
After an overnight fast of at least 10 hours, the test product was administered orally (10 mg) to sitting subjects in a single dose with 20 ± 02 mL of drinking water at an ambient temperature to wet the mouth immediately prior to administration. IMP administration was performed under open-label conditions according to a randomized schedule. Subjects were asked to keep the tablets in their mouths, do not swallow them, and do not chew, bite, or break the tablets until they were completely disintegrated.

Reference sample:
After an overnight fast of at least 10 hours, the reference product was orally administered (10 mg) to a sitting subject with 240 ± 02 mL of drinking water at ambient temperature. IMP administration was performed under open-label conditions according to a randomized schedule. I swallowed the tablets without chewing or crushing them.

sampling:
Blood was collected at the initial time and at each time point after administration.

Blood samples were taken via an endogenous intravenous cannula (Benflon) placed in the subject's forearm vein. A blood sample was taken 24 hours after administration and the cannula was removed. Blood samples 24 hours after dosing were taken through a new venipuncture. Blood samples for outpatient samples for each period were collected using new venipuncture. Immediately after blood collection, the blood collection tube (vacutainer) was gently inverted several times to ensure that the contents of the tube (ie, anticoagulant) were mixed. For prophylaxis, the vacutainer was erected in a rack held in an ice-cold water bath until it was centrifuged.

Blood samples were centrifuged at 3000 rcf for 5 minutes below 10 ° C. to separate plasma. For prophylaxis, blood samples were kept in an ice-cold water bath before and during centrifugation. The separated plasma was transferred to a polypropylene tube pre-labeled with two aliquots (approximately 0.4 mL for the first aliquot and the remaining volume for the second aliquot).

All samples were stored upright in the freezer at a temperature of -65 ± 10 ° C. and provisionally stored until transferred to the bioanalytical department.

F. Pharmacokinetic Results The pharmacokinetic parameters of solifenacin for test product-T and reference product-R are summarized in the table below:

The relative bioavailability analysis of solifenacin test product-T and reference product-R (ie, geometric least squares mean, ratio, 90% confidence interval, intrasubject CV and power) is summarized in the following table.

The results in Table 13 show that when the solid oral dosage form of the invention (test product-T) is compared to Bioavailability® 10 mg (reference product-R), hunger conditions are based on the criteria set by the protocol. It shows that it meets the bioavailability criteria for _{C max} and AUC _0-t of solifenacin. The solid oral dosage form of the present invention is then bioequivalent to the reference product (Vesicale®).

FIG. 4 shows the mean plasma concentration-time curve of the solid oral dosage form vs. reference product Vesicare® of the present invention. FIG. 4 shows that the dosage form of the invention is different from that of the reference product, despite the fact that the dissolution profile of the composition of the invention at oral and gastric pH is significantly different from that of the reference product (FIGS. 2 and 3). It emphasizes that it shows a very similar bioavailability profile in comparison.

Reference list European Pharmacopoeia 6.0, 750 European Pharmacopoeia 6.0, 263 European Pharmacopoeia 6.0, 278-279 Guidelines for impurities in pharmaceuticals among new active ingredient-containing drugs Q3B (R2)
European Patent Publication No. 1787640A1 Publication European Patent Publication No. 1728791A1 Publication Rami Reddy B.I. V. , Devopment and Validation of a Special Physical Indicatoring High Performance Liquid Chromatographic Metrics for Related Compound Assay 20 ID412353, page 7 Klauwinkel W. et al. J. J. , Effect of age on the pharmacokinetics of solifenacin in men and women, Int J Clin Pharmacol Ther. , 2005; Vol. 43, pp. 227-238. , Issues in the formulation of drugs for oral use in children: Role of excipients, Paediatr Drugs, 2002; 4 (6), pp. 371-379, Eadala P. et al. , Quantifying the “hidden” lactose in drugs used for the treatment of gastrointestinal conditions, Aliment Pharmacol. The. , 2009, Vol. 29, pp. 677-687

For completeness reasons, various aspects of the invention are set forth in the numbered provisions below.

Clause 1 A pharmaceutical solid oral dosage form containing a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt or polymer thereof, and one or more pharmaceutically acceptable excipients or carriers thereof, the solifenacin or its pharmaceutically acceptable dosage form. A pharmaceutical solid oral dosage form characterized in that a pharmaceutically acceptable salt and the polymer form a matrix and the dosage form exhibits a dissolution profile according to the following:
(I) After 5 minutes at pH 6.5-7.5, less than 10 w / w% of solifenacin content dissolves, and (ii) after 30 minutes at pH 1.0-1.6, 80 w / w / of solifenacin content. Over w% dissolves,
(The dissolution profile is determined using the European Pharmacopoeia Instrument II (paddle), placing the dosage form in 900 mL under appropriate pH conditions and stirring at 37 ° C. and 50 rpm.)
Item 2. The dosage form according to item 1, wherein the pharmaceutical solid oral dosage form is a tablet, preferably an orally disintegrating tablet.
Item 3. The dosage form according to Item 1 to 2, wherein the polymer is an ion exchange resin.
Item 4. The dosage form according to Item 1 to 3, wherein the polymer is a cation exchange resin.
Item 5. The dosage form according to Item 1 to 4, wherein the polymer is an acidic or weakly acidic cation exchange resin.
Item 6. The dosage form according to Item 1 to 5, wherein the polymer is a methacrylic acid-divinylbenzene copolymer.
Item 7. The dosage form according to Item 1 to Item 6, wherein the polymer is a partial potassium salt of a methacrylic acid-divinylbenzene copolymer.
Item 8. The dosage form according to Item 1 to Item 7, wherein the polymer is potassium polarkrillin.
Item 9. The dosage form according to item 8, wherein the potassium polacrilin is Purolite® C115KMR.
Item 10. The dosage form according to item 1 to 9, wherein the dissolution profile is shown according to the following items:
(I) After 5 minutes at pH 6.5-7.5, less than 5 w / w% of solifenacin content dissolves, and (ii) after 30 minutes at pH 1.0-1.6, 80 w / w / of solifenacin content. More than w% dissolves.
11. The dosage form according to paragraphs 1 to 10, characterized in that it exhibits a dissolution profile according to the following.
(I) After 5 minutes at pH 6.5-7.5, less than 3 w / w% of solifenacin content dissolves, and (ii) after 30 minutes at pH 1.0-1.6, 80 w / w / of solifenacin content. More than w% dissolves.
12. The dosage form according to paragraphs 1 to 11, characterized in that it exhibits a dissolution profile according to paragraph 12 et seq.
(I) After 5 minutes at pH 6.5-7.5, less than 2 w / w% of solifenacin content dissolves, and (ii) after 30 minutes at pH 1.0-1.6, 80 w / w / of solifenacin content. More than w% dissolves.
Clause 13 Disintegration time is determined by European Pharmacopoeia Test A, dosage form at 37 ° C., 30 cycles / min, within 3 minutes at pH 6.5-7.5. The dosage form according to any one of paragraphs 1 to 12, wherein the dosage form is characterized by the above.
14. The dosage form according to paragraph 13, characterized in that it disintegrates within 2 minutes at pH 6.5-7.5.
15. The dosage form of paragraphs 13-14, characterized in that it disintegrates within 1 minute at pH 6.5-7.5.
16. The dosage form according to paragraphs 1 to 15, characterized in that it contains an amorphous substance of solifenacin or other pharmaceutically acceptable salt thereof in a content of more than 77 w / w%.
17. The dosage form according to paragraphs 1 to 15, characterized in that it contains an amorphous substance of solifenacin or other pharmaceutically acceptable salt thereof in a content of more than 80 w / w%.
18. The dosage form according to paragraphs 1 to 15, characterized in that it contains an amorphous substance of solifenacin or other pharmaceutically acceptable salt thereof in a content of more than 90 w / w%.
Clause 19 Content of more than 77 w / w% amorphous of solifenacin or other pharmaceutically acceptable salt thereof after 3 months of storage under conditions of temperature 20-30 ° C. and relative humidity 55-65%. The dosage form according to paragraph 16, wherein the dosage form is contained in.
Item 20 Content of more than 80 w / w% amorphous of solifenacin or other pharmaceutically acceptable salt thereof after 3 months of storage under conditions of temperature of 20-30 ° C. and relative humidity of 55-65%. The dosage form according to paragraph 17, wherein the dosage form is contained in.
Clause 21 Content of more than 90 w / w% amorphous of solifenacin or other pharmaceutically acceptable salt thereof after 3 months of storage under conditions of temperature 20-30 ° C. and relative humidity 55-65%. The dosage form according to paragraph 18, wherein the dosage form comprises.
Item 22. Item 16-. The dosage form according to item 21.
Item 23. Item 16-. The dosage form according to item 21.
Item 24. Item 16-. The dosage form according to item 21.
25. 16-18, characterized by containing less than 0.5% solifenacin N-oxide after 3 months of storage at a temperature of 30-40 ° C. and a relative humidity of 65-75%. Dosage form described in.
26. 16-18, characterized by containing less than 0.2% solifenacin N-oxide after 3 months of storage at a temperature of 30-40 ° C. and a relative humidity of 65-75%. Dosage form described in.
27. 16-18, characterized by containing less than 0.1% solifenacin N-oxide after 3 months of storage at a temperature of 30-40 ° C. and a relative humidity of 65-75%. Dosage form described in.
28. 16-., Which comprises less than 0.5 w / w% solifenacin N-oxide after 6 months of storage at a temperature of 20-30 ° C and a relative humidity of 55-65%. The dosage form according to item 21.
Item 29. Item 16-. The dosage form according to item 21.
Item 30. Item 16-. The dosage form according to item 21.
31. 16-18, characterized by containing less than 0.5% solifenacin N-oxide after 6 months of storage at a temperature of 30-40 ° C. and a relative humidity of 65-75%. Dosage form described in.
32. 16-18, characterized by containing less than 0.2% solifenacin N-oxide after 6 months of storage at a temperature of 30-40 ° C. and a relative humidity of 65-75%. Dosage form described in.
33. 16-18, characterized by containing less than 0.1% solifenacin N-oxide after 6 months of storage at a temperature of 30-40 ° C. and a relative humidity of 65-75%. Dosage form described in.
34. Items 1 to 33, wherein the polymer is present in a weight-to-weight ratio of solifenacin or a pharmaceutically acceptable salt thereof to the polymer at a weight-to-weight ratio of 0.5: 1 to 1:10. The dosage form described in the section.
35. The polymer is present in a weight-to-weight ratio of solifenacin or a pharmaceutically acceptable salt thereof to the polymer in a weight-to-weight ratio of 1: 1 to 1: 4. The dosage form described.
Item 36. Item 1 to 33, wherein the polymer is present in a weight-to-weight ratio of solifenacin or a pharmaceutically acceptable salt thereof to the polymer in a weight-to-weight ratio of 1: 1.5 to 1: 3. The dosage form described in the section.
37. The dosage form according to paragraphs 1 to 33, wherein the polymer is present in a weight-to-weight ratio of 1: 2 of solifenacin or a pharmaceutically acceptable salt thereof to the polymer. ..
38. The dosage form according to any one of 34 to 37, wherein the polymer is an ion exchange resin.
39. The dosage form according to claim 34-38, wherein the polymer is a cation exchange resin.
Item 40. The dosage form according to Item 34 to 39, wherein the polymer is an acidic or weakly acidic cation exchange resin.
41. The dosage form according to any one of 34 to 40, wherein the polymer is a methacrylic acid-divinylbenzene copolymer.
42. The dosage form according to any one of 34 to 41, wherein the polymer is a potassium salt or a partial potassium salt of a methacrylic acid-divinylbenzene copolymer.
43. The dosage form of paragraphs 34-42, wherein the polymer is potassium polarkrillin.
44. The dosage form of paragraphs 34-43, wherein the polymer is Purplete® C115KMR.
Item 45 Extragranular and intragranular disintegration of the pharmaceutically acceptable excipient selected from polyvinylpolypyrrolidone (crospovidone), crosslinked carboxymethyl cellulose (croscarmellose), starch glycolate or mixtures thereof. The dosage form according to any one of paragraphs 1 to 44, which comprises an agent.
46. The dosage form according to claim 45, wherein the total amount of the extragranular and intragranular disintegrant is present in an amount of 1 to 35% by weight of the disintegrant in the dosage form.
47. The dosage form according to claim 45 to 46, wherein the total amount of the extragranular and intragranular disintegrant is present in an amount of 10 to 30% by weight of the disintegrant in the dosage form.
48. The dosage form according to paragraph 45-47, wherein the total amount of the extragranular and intragranular disintegrant is present in an amount of 20-28% by weight of the disintegrant in the dosage form.
49. The dosage form of paragraphs 45-48, wherein the disintegrant is present in a weight-to-weight ratio of intragranular disintegrant to extragranular disintegrant 14: 1 to 1:14. ..
Item 50. The dosage form according to Item 49, wherein the disintegrant is present at a weight-to-weight ratio of 13: 2 to 2:13 for the intragranular disintegrant to the extragranular disintegrant.
51. The dosage form according to any one of 49 to 50, wherein the disintegrant is present at a weight-to-weight ratio of 13: 2 to 2:13 for the intragranular disintegrant to the extragranular disintegrant. ..
52. The dosage form according to any one of 49 to 51, wherein the disintegrant is present in a weight-to-weight ratio of an intragranular disintegrant to an extragranular disintegrant of 2: 1 to 1: 4. ..
Item 53: The method for preparing a solid oral dosage form according to any one of Items 1 to 52, which comprises the following steps:
(A) A step of preparing a mixture of solifenacin or a pharmaceutically acceptable salt thereof in water and a polymer.
(B) The step of mixing one or more diluents and optionally one or more binders, disintegrants, sweets, flavors, or other excipients or carriers.
(C) A step of granulating the mixture of step (b) by adding the liquid mixture of step (a) to obtain wet granules.
(D) A step of drying the wet granules obtained in the step (c) to obtain dried granules.
(E) The dried granules obtained in step (d) are added to one or more lubricants and optionally one or more diluents, binders, disintegrants, sweeteners and flavors, or other additives. The process of mixing with a shaper or carrier,
(F) A step of compressing the mixture obtained in step (e) to form a tablet.
54. The method of claim 53, wherein the polymer of step (a) is an ion exchange resin.
55. The method of paragraphs 53-54, wherein the polymer of step (a) is a cation exchange resin.
56. The method of paragraphs 53-55, wherein the polymer of step (a) is an acidic or weakly acidic cation exchange resin.
57. The method of paragraphs 53-56, wherein the polymer of step (a) is an acidic or weakly acidic cation exchange resin.
58. The method of paragraphs 53-57, wherein the polymer of step (a) is a methacrylic acid-divinylbenzene copolymer.
59. The method of paragraphs 53-58, wherein the polymer of step (a) is a potassium salt or a partial potassium salt of a methacrylic acid-divinylbenzene copolymer.
Item 60. The method according to paragraph 53 to 59, wherein the polymer of step (a) is potassium polarkrillin.
Clause 61 One or more disintegrants of steps (b) and (e) are selected from polyvinylpolypyrrolidone (crospovidone), crosslinked carboxymethyl cellulose (croscarmellose), starch glycolate, or mixtures thereof. The method according to any one of 53 to 60, wherein the method is characterized by the above.
62. The solid oral dosage form according to any one of paragraphs 1 to 52, which can be obtained by the method according to any one of paragraphs 53 to 61.
63. The solid oral dosage form according to any one of paragraphs 1 to 52 and 62 for use in the treatment of lower urinary tract symptoms associated with overactive bladder syndrome.
64. The use according to paragraph 63, wherein the lower urinary tract symptoms associated with overactive bladder syndrome are selected from the group consisting of urge incontinence, increased urinary frequency and increased urgency. Solid oral dosage form for.

Claims (18)

An orally disintegrating pharmaceutical solid dosage form containing a therapeutically effective amount of soriphenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers. Alternatively, an orally disintegrating pharmaceutical solid dosage form characterized in that a pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, and the dosage form exhibits a dissolution profile according to the following. :
When determined using the European Pharmacopoeia Device II (paddle), the dosage form in 900 mL under appropriate pH conditions and stirring at 37 ° C. and 50 rpm.
(I) After 5 minutes at pH 6.5-7.5, less than 10 w / w% of the solifenacin content dissolves, and (ii) after 30 minutes at pH 1.0-1.6, the solifenacin content. More than 80w / w% dissolves,
Orally disintegrating pharmaceutical solid dosage form. The dosage form according to claim 1, wherein the ion exchange resin is a methacrylic acid-divinylbenzene copolymer. The dosage form according to claim 1 or 2, wherein the ion exchange resin is potassium polarkrillin. The dosage form according to claims 1-3, which comprises one or more disintegrants in an amount of 1-35 w / w%. The dosage form according to claim 4, wherein the one or more disintegrants are crosslink disintegrants. The dosage form according to claim 1 to 5, which is an orally disintegrating tablet. The dosage form according to claim 6, characterized in that it exhibits a hardness of 70 N or less, preferably 60 N or less, more preferably 50 N or less. When the dosage form was placed in phosphate buffer having pH = 7 and measured at 37 ° C. and 30 cycles per minute using the European Pharmacopoeia Disintegrator A, within 3 minutes, especially within 2 and a half minutes, and more. The dosage form according to claim 1, wherein the dosage form disintegrates within 2 minutes in detail, and more specifically within 1 minute. Dissolution profile according to
(I) After 5 minutes at pH 6.5-7.5, less than 5 w / w% of the solifenacin content dissolves, and (ii) after 30 minutes at pH 1.0-1.6, the solifenacin content. More than 80w / w% of
The dosage form according to claim 1 to 8, wherein the dosage form is characterized by the above. Dissolution profile according to
(I) After 5 minutes at pH 6.5-7.5, less than 3 w / w% of the solifenacin content dissolves, and (ii) after 30 minutes at pH 1.0-1.6, the solifenacin content. More than 80w / w% of
The dosage form according to claim 1 to 9, wherein the dosage form is characterized by the above. The dosage form according to claim 1-10, which comprises lactose in a weight-to-weight ratio of solifenacin to lactose of 1: 1 to 1:10 and exhibits a degree of wear of less than 1%. The dosage form of claims 1-11, characterized in that it comprises an amorphous solifenacin or other pharmaceutically acceptable salt thereof in a content of greater than 77 w / w%. Amorphous content of solifenacin or other pharmaceutically acceptable salt thereof in excess of 77 w / w% after 3 months of storage under conditions of temperature of 20-30 ° C. and relative humidity of 55-65%. 12. The dosage form according to claim 12. 12-13. Dosage form. The dosage form according to claim 1 to 14, wherein the ion exchange resin is present in a weight-to-weight ratio of 1: 2 between soriphenacin or a pharmaceutically acceptable salt thereof and the ion exchange resin. The following steps,
(A) A step of preparing a mixture of solifenacin or a pharmaceutically acceptable salt thereof and an ion exchange resin in water.
(B) The step of mixing one or more diluents and optionally one or more binders, disintegrants, sweets, flavors, or other excipients or carriers.
(C) A step of granulating the mixture of step (b) by adding the liquid mixture of step (a) to obtain wet granules.
(D) A step of drying the wet granules obtained in the step (c) to obtain dried granules.
(E) The dried granules obtained in step (d) are added to one or more lubricants and optionally one or more diluents, binders, disintegrants, sweeteners and flavors, or other additives. The process of mixing with a shaper or carrier,
(F) A step of compressing the mixture obtained in step (e) to form a solid oral dosage form.
The method for preparing a solid oral dosage form according to any one of claims 1 to 15. 16. The method of claim 16, wherein the drying step (d) is performed under vacuum conditions. The solid oral dosage form according to any one of claims 1 to 15, for use in the treatment of lower urinary tract symptoms associated with overactive bladder syndrome.

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